Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal lung disease characterized by the overgrowth, hardening, and scarring of lung tissue. The exact mechanisms of how IPF develops and progresses are unknown. IPF is characterized by extracellular matrix remodeling and accumulation of active TGFβ, which promotes collagen expression and the differentiation of smooth muscle α-actin (SMA)-positive myofibroblasts. Aortic carboxypeptidase-like protein (ACLP) is an extracellular matrix protein secreted by fibroblasts and myofibroblasts and is expressed in fibrotic human lung tissue and in mice with bleomycin-induced fibrosis. Importantly, ACLP knockout mice are significantly protected from bleomycin-induced fibrosis. The goal of this study was to identify the mechanisms of ACLP action on fibroblast differentiation. As primary lung fibroblasts differentiated into myofibroblasts, ACLP expression preceded SMA and collagen expression. Recombinant ACLP induced SMA and collagen expression in mouse and human lung fibroblasts. Knockdown of ACLP slowed the fibroblast-to-myofibroblast transition and partially reverted differentiated myofibroblasts by reducing SMA expression. We hypothesized that ACLP stimulates myofibroblast formation partly through activating TGFβ signaling. Treatment of fibroblasts with recombinant ACLP induced phosphorylation and nuclear translocation of Smad3. This phosphorylation and induction of SMA was dependent on TGFβ receptor binding and kinase activity. ACLP-induced collagen expression was independent of interaction with the TGFβ receptor. These findings indicate that ACLP stimulates the fibroblast-to-myofibroblast transition by promoting SMA expression via TGFβ signaling and promoting collagen expression through a TGFβ receptor-independent pathway.
Highlights
On the basis of these results and our prior in vivo studies correlating a loss of Aortic carboxypeptidase-like protein (ACLP) with a reduction in lung fibrosis [25], we hypothesized that ACLP promotes the fibroblast-to-myofibroblast transition
This study identified a novel mechanism by which ACLP controls lung myofibroblast differentiation
We discovered that ACLP interacts with and activates TGF receptors and stimulates downstream Smad3 signal transduction pathways to enhance smooth muscle ␣-actin (SMA) expression and signals through an Myofibroblast Differentiation (MRTFA)-independent pathway to promote collagen expression
Summary
Results: Aortic carboxypeptidase-like protein (ACLP) stimulates myofibroblast differentiation through activation of transforming growth factor  receptor signaling. IPF is characterized by extracellular matrix remodeling and accumulation of active TGF, which promotes collagen expression and the differentiation of smooth muscle ␣-actin (SMA)-positive myofibroblasts. Aortic carboxypeptidase-like protein (ACLP) is an extracellular matrix protein secreted by fibroblasts and myofibroblasts and is expressed in fibrotic human lung tissue and in mice with bleomycin-induced fibrosis. Recombinant ACLP induced SMA and collagen expression in mouse and human lung fibroblasts. We hypothesized that ACLP stimulates myofibroblast formation partly through activating TGF signaling. Treatment of fibroblasts with recombinant ACLP induced phosphorylation and nuclear translocation of Smad3 This phosphorylation and induction of SMA was dependent on TGF receptor binding and kinase activity. ACLP-induced collagen expression was independent of interaction with the TGF receptor. These findings indicate that ACLP stimulates the fibroblast-to-myofibroblast transition by promoting SMA expression via TGF signaling and promoting collagen expression through a TGF receptor-independent pathway
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